Immune Netw.  2013 Dec;13(6):289-294. 10.4110/in.2013.13.6.289.

Acute Phase Protein Lipocalin-2 Is Associated with Formalin-induced Nociception and Pathological Pain

• Jha MK
• Jeon S
• Jin M
• Lee WH
• Suk K

• KMID: 2150790
• DOI: http://doi.org/10.4110/in.2013.13.6.289

Abstract

Lipocalin-2 (LCN2) is an acute-phase protein induced by injury, infection, or other inflammatory stimuli. LCN2 binds small hydrophobic ligands and interacts with cell surface receptor to regulate diverse cellular processes. The role of LCN2 as a chemokine inducer in the central nervous system (CNS) has been previously reported. Based on the previous participation of LCN2 in neuroinflammation, we investigated the role of LCN2 in formalin-induced nociception and pathological pain. Formalin-induced nociceptive behaviors (licking/biting) and spinal microglial activation were significantly reduced in the second or late phase of the formalin test in Lcn2 knockout mice. Likewise, antibody-mediated neutralization of spinal LCN2 attenuated the mechanical hypersensitivity induced by peripheral nerve injury in mice. Taken together, our results suggest that LCN2 can be therapeutically targeted, presumably for both prevention and reversal of acute inflammatory pain as well as pathological pain.

Keyword

Lipocalin-2; Acute nociception; Pathological pain; Neuroinflammation; Microglia; Spinal cord

MeSH Terms

Acute-Phase Proteins*
Animals
Central Nervous System
Hypersensitivity
Ligands
Mice
Mice, Knockout
Microglia
Nociception*
Pain Measurement
Peripheral Nerve Injuries
Spinal Cord
Acute-Phase Proteins
Ligands

Figure

• 

  Figure 1 Attenuation of acute inflammatory pain in Lcn2 KO mice. (A) Formalin (5%, 10 µl) is administered intraplantarly to the left hindpaw of mice, then nociceptive behavior is measured as shown in the experimental timeline. (B) The behaviors of wild-type (WT) and Lcn2 KO mice are compared for 40 min after the injection. Times spent licking or biting injected hindpaws are recorded. (C) The first 10 min post-injection is defined as the early phase, and the period between 15 and 40 min post-injection as the late phase. The results are means±SEMs. *p<0.05, n.s.=not significant (n=7~9).

• 

  Figure 2 Reduction of microglial activation in Lcn2 KO mice. (A) The lumbar segment (L4-6) of the spinal cord is sampled 30 min after the intraplantar injection of formalin (5%, 10 µl) as shown in the experimental timeline. (B) Photomicrographs showing Iba-1 immunoreactivity in the dorsal horns of the ipsilateral lumbar spinal cords of WT and Lcn2 KO mice. The results are representative of at least three independent experiments. Scale bars=200 µm.

• 

  Figure 3 Spinal LCN2 neutralization attenuated SNI-induced pain behavior. (A) LCN2 antibody (0.1 µg/µl, 10 µl), or the same volume of vehicle, is injected intrathecally 30 min before SNI surgery, and the pain test was performed as shown in the experimental timeline. (B) In the ipsilateral side, SNI significantly reduces the paw withdrawal threshold (PWT) to force. The SNI-induced decrease in PWT is significantly attenuated in the LCN2-neutralized mice compared with control animals at 1 day and 2 days after SNI surgery. No significant change in pain-related behavior is observed in the contralateral side. The results are means±SEMs. *p<0.05 versus the vehicle (PBS) group (n=3).

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